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Hereditary neuropathy NOT PMP22 copy number

Gene: RFC1

Red List (low evidence)

RFC1 (replication factor C subunit 1)
EnsemblGeneIds (GRCh38): ENSG00000035928
EnsemblGeneIds (GRCh37): ENSG00000035928
OMIM: 102579, Gene2Phenotype
RFC1 is in 2 panels

4 reviews

Dmitrijs Rots (RadboudUMC)

Red List (low evidence)

Only STR in this gene is associated with CANVAS / ataxia. Addition of this gene to the panel will result only in unnecessary load of RFC1 SNV/indel/CNV analysis, which are not related to human disorder.
Additionallly, RFC1 repeat expansion, is commonly associated with sensory neuropathy (at the moment of presentation usually without clinically prominent ataxia) ,so the STR should be added to the neuropathy panel as well, not just ataxia (PMID: 33969391).
Created: 2 Dec 2021, 11:38 a.m. | Last Modified: 2 Dec 2021, 11:40 a.m.
Panel Version: 2.133

Eleanor Williams (Genomics England Curator)

I don't know

Copied this gene from the Hereditary ataxia - adult onset panel so that it is noted that the STR associated with this gene is relevant to the panel, NOT SNV/indels or deletions covering this gene. In PMID: 33969391 - Curro et al 2021 - they found that 43 patients (34%) with sensory neuropathy had biallelic AAGGG repeat expansions in RFC1and in none with sensory-motor neuropathy.
Created: 7 Dec 2021, 3:36 p.m. | Last Modified: 7 Dec 2021, 3:36 p.m.
Panel Version: 1.68
Comment on list classification: Changing the rating from amber to red so that it is clear that this gene should not be added to the panel as it is an STR within an intron of this gene that is associated with the neuropathy phenotype.
Created: 7 Dec 2021, 3:29 p.m. | Last Modified: 7 Dec 2021, 3:29 p.m.
Panel Version: 2.134
Comment on list classification: Promoting this gene from grey to amber, but noting that it is repeat expansions within an intron that is associated with the CANVAS phenotype, not SNVs within the protein coding region. Added to the list of STRs to be added.
Created: 1 Dec 2021, 5:23 p.m. | Last Modified: 1 Dec 2021, 5:23 p.m.
Panel Version: 2.133
The gene is associated with Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) #614575 (AR) with two repeat expansions cited as the allelic variants.

There is data to suggest a common haplotype between most cases but this appears to be quite ancient (25000 yo) and so the cases from individuals from different countries can probably be counted as being unrelated. The mechanism of action of this intronic repeat expansion is not yet known.

= AAGGG repeat expansion =

PMID: 30926972 - Cortese et al 2019 - found a recessive intronic AAGGG repeat expansion in the RFC1 gene as a cause of familial CANVAS in 11 families. 4 SNPs around RFC1 were shared by all individuals except in family 5, suggesting a founder haplotype. They found an additional 33 sporadic cases carrying the recessive AAGGG repeat expansion in a cohort of 150 patients diagnosed with sporadic late-onset ataxia (22%). They also note that all sporadic cases with the repeat expansion, except for one individual, shared the same haplotype as familial CANVAS cases. Although the expansion size varied across different families, ranging from around 400 to 2000 repeats, in the majority of cases approximately 1000 repeats were observed. In 304 healthy controls, 4/608 chromosomes (0.7%) chromosomes carried an AAGGG expansion in the heterozygous state. 3 other conformations were observed: (AAAAG)11 (75.5%); (AAAAG)exp(13.0%); and (AAAGG)exp (7.9%). They did not observe a reduced level of RFC1 expression at either the transcript or the protein level in CANVAS patients.

PMID: 31824583 - Akçimen et al 2019 - looked at RFC1 repeat expansions in cohort of Brazilian cases and two cohorts of Canadian cases. 1 Brazilian and 1 Canadian case were found to carry the causative biallelic AAGGG repeat expansion. Two novel repeat sequences were found in the heterozygous state; AAGAG and AGAGG.

PMID: 31230722 - Rafehi et al 2019 - bioinformatics paper looking at using Expansion Hunter de novo on WGS data but also reports RFC1 (AAGGG)exp in 18/22 CANVAS families. Also states that the core ancestral haplotype is estimated to have arisen in Europe more than twenty-five thousand years ago.

PMID: 32851396 - Beecroft et al 2020 - describe a (AAAGG)10-25(AAGGG)exp found in New Zealand Māori and Cook Island Māori individuals which was the cause of CANVAS in all patients. Patients in 2 families also had small number of repeats of the benign variant allele (AAAGG)4-6 at the distal end of the RFC1 pathogenic expansion. The 4 patients with WGS data were found to share the same core haplotype as described in European populations in Cortese et al 2019, plus an additional region.

PMID: 32582864 - Syriani et al 2020 - 29 patients from North America were identified with biallelic repeat expansions in RFC1 (AAGGG) (3.2% of total). Of these 29 patients, 8 (28%) had a clinical diagnosis of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS), 14 had cerebellar ataxia with neuropathy (48%), 4 had pure cerebellar ataxia (14%).

PMID: 32694621 - Tsuchiya et al 2020 - found intronic (AAGGG) repeat expansions in RFC1 in 3 (12%) of the familial Japanese patients with CANVAS and 1 (8.5%) of the sporadic ones.

PMID: 33969391 - Curro et al 2021 - retrospectively identified 225 patients diagnosed with chronic idiopathic axonal polyneuropathy (125 sensory neuropathy, 100 sensory-motor neuropathy). Patients previously diagnosed with CANVAS or with a family history of CANVAS were not included. 43 patients (34%) with sensory neuropathy had biallelic AAGGG repeat expansions in RFC1and in none with sensory-motor neuropathy.

= ACAGG repeat expansion =

PMID: 33103729 - Scriba et al 2020 - report 3 patients with CANVAS from 2 families (2 brothers who reside in Indonesia, but are of Chinese descent, and a isolated female proband from the island nation of Niue) , with a novel, likely pathogenic RFC1 repeat motif (ACAGG)exp. These patients show additional clinical features including fasciculations and elevated creatine kinase levels. They share the core haplotype described in Cortese et al 2019 and Beecroft et al 2020. The RFC1 (ACAGG) motif was found in 7 individuals from 26 745 samples from gnomAD v3; 2 African, 4 South Asian, 1 East Asian.

PMID: 32694621 - Tsuchiya et al 2020 - reports a RFC1 (ACAGG) exp in 1 Japanese individual with sporadic CANVAS.
Created: 1 Dec 2021, 12:38 p.m. | Last Modified: 1 Dec 2021, 5:20 p.m.
Panel Version: 2.130

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome, OMIM:614575; cerebellar ataxia, neuropathy, and vestibular areflexia syndrome, MONDO:0013809; chronic idiopathic axonal polyneuropathy; chronic polyneuropathy, MONDO:0003335

Publications

Michael Bonello (The Walton Centre NHS Foundation Trust)

Green List (high evidence)

Further evidence of diagnostic link of RFC1 intronic expansion with CANVAS Syndrome, Cerebellar ataxia and Idiopathic Sensory neuropathy
Created: 12 Nov 2021, 2:06 p.m. | Last Modified: 12 Nov 2021, 2:06 p.m.
Panel Version: 2.126

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
CANVAS Syndrome; Cerebellar ataxia; Idiopathic Sensory Neuropathy

Publications

Mode of pathogenicity
Other

Variants in this GENE are reported as part of current diagnostic practice

Zornitza Stark (Australian Genomics)

Green List (high evidence)

A novel RFC1 repeat motif (ACAGG) in two Asia-Pacific CANVAS families reported in PMID 33103729. Both of these need to be added as STRs but I haven't quite figured out how to do it!
Created: 9 Dec 2020, 7:55 a.m. | Last Modified: 9 Dec 2020, 7:55 a.m.
Panel Version: 2.17
23 affected individuals from 11 families reported with biallelic AAGGG repeat expansion in intron 2. Expansion carrier frequency of 0.7% in Europeans.
Sources: Expert Review
Created: 2 Apr 2020, 9:34 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome OMIM 614575

Publications

Mode of pathogenicity
Other

Variants in this GENE are reported as part of current diagnostic practice

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review
  • Expert Review Red
Phenotypes
  • Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome, OMIM:614575
  • cerebellar ataxia, neuropathy, and vestibular areflexia syndrome, MONDO:0013809
  • chronic idiopathic axonal polyneuropathy
  • chronic polyneuropathy, MONDO:0003335
Tags
STR
OMIM
102579
Clinvar variants
Variants in RFC1
Penetrance
None
Publications
Mode of Pathogenicity
Other
Panels with this gene

History Filter Activity

7 Dec 2021, Gel status: 1

Created, Added New Source, Added Tag, Set mode of inheritance, Set publications, Set Phenotypes, Set mode of pathogenicity

Eleanor Williams (Genomics England Curator)

gene: RFC1 was added gene: RFC1 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Expert Review Red,Expert Review STR tags were added to gene: RFC1. Mode of inheritance for gene: RFC1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RFC1 were set to 30926972; 31824583; 32851396; 32582864; 33969391 Phenotypes for gene: RFC1 were set to Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome, OMIM:614575; cerebellar ataxia, neuropathy, and vestibular areflexia syndrome, MONDO:0013809; chronic idiopathic axonal polyneuropathy; chronic polyneuropathy, MONDO:0003335 Mode of pathogenicity for gene: RFC1 was set to Other